US4587256A - Novel thiazolidine derivatives - Google Patents

Novel thiazolidine derivatives Download PDF

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Publication number
US4587256A
US4587256A US06/619,655 US61965584A US4587256A US 4587256 A US4587256 A US 4587256A US 61965584 A US61965584 A US 61965584A US 4587256 A US4587256 A US 4587256A
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US
United States
Prior art keywords
benzopyran
fluoro
thiazolidine
compound
dihydro
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Fee Related
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US06/619,655
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English (en)
Inventor
Heinz Hasler
Fernand Schneider
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Hoffmann La Roche Inc
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Hoffmann La Roche Inc
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Assigned to HOFFMANN-LA ROCHE INC., NUTLEY, NJ A CORP OF reassignment HOFFMANN-LA ROCHE INC., NUTLEY, NJ A CORP OF ASSIGNMENT OF ASSIGNORS INTEREST. Assignors: F. HOFFMANN-LA ROCHE & CO. AKTIENGESELLSCHAFT
Assigned to F. HOFFMANN-LA ROCHE & CO., AKTIENGESELLSCHAFT reassignment F. HOFFMANN-LA ROCHE & CO., AKTIENGESELLSCHAFT ASSIGNMENT OF ASSIGNORS INTEREST. Assignors: HASLER, HEINZ, SCHNEIDER, FERNAND
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/08—Preparation of carboxylic acids or their salts, halides or anhydrides from nitriles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/10—Spiro-condensed systems

Definitions

  • the invention relates to thiazolidine derivatives of the formula ##STR2## wherein X is methylene, oxygen or sulfur; R 1 is halogen; R 2 is hydrogen, nitro, cyano, OR 3 or NHR 3 ; or R 1 and R 2 both simultaneously are hydrogen or nitro; R 3 is hydrogen, alkyl, acyl, --CO--OR 4 or --CO--NHR 4 ; and R 4 is alkyl, unsubstituted or substituted aryl or aralkyl;
  • the compounds of formula I are useful in the treatment of diabetes mellitus.
  • the invention relates to a process for the preparation of the compounds of formula I and of salts thereof, pharmaceutical preparations containing the compounds of formula I as well as their use as medicaments, especially in the treatment of metabolic illnesses.
  • the invention relates to thiazolidine derivatives of the formula ##STR3## wherein X is methylene, oxygen or sulfur; R 1 is halogen; R 2 is hydrogen, nitro, cyano, OR 3 or NHR 3 ; or R 1 and R 2 both simultaneously are hydrogen or nitro; R 3 is hydrogen, alkyl, acyl, --CO--OR 4 or --CO--NHR 4 ; and R 4 is alkyl, unsubstituted or substituted aryl or aralkyl,
  • halogen denotes chlorine, fluorine, bromine and iodine
  • the preferred substituents are fluorine and chlorine.
  • Alkyl groups can be straight-chain or branched-chain and preferably containing 1-12 carbon atoms. Examples of such groups are methyl, ethyl, propyl, butyl, pentyl, hexyl, decyl, dodecyl and the like.
  • Acyl denotes, preferably, alkanoyl containing 1-12 carbon atoms and aroyl containing 7 to 14 carbon atoms, such aryl groups can be derived from carboxylic acids, for example, aliphatic, aromatic or araliphatic carboxylic acids which preferably contain 1-12 carbon atoms such as acetic acid, propionic acid, butyric acid, caproic acid, undecanoic acid, dodecanoic acid, acetoacetic acid, acetylglycolic acid, benzoic acid, substituted benzoic acids such as p-toluic acid, p-nitrobenzoic acid, p-chlorobenzoic acid, p-bromobenzoic acid and m-dinitrobenzoic acid; naphthoic acid, phenylacetic acid; or aliphatic or aromatic sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid
  • Alkyl groups denoted by R 4 preferably contain 1-6 carbon atoms, examples, methyl, ethyl, propyl, isopropyl, butyl and isobutyl.
  • aryl groups are phenyl and substituted phenyl groups such as halophenyl, nitrophenyl and alkoxycarbonylphenyl.
  • aralkyl group are C 1-6 -alkyl groups which are substituted by one of the aforementioned aryl groups, for example, benzyl and nitrobenzyl.
  • physiologically compatible cations are alkali metal and alkaline earth metal ions, such as, Na + , K + , Ca ++ , Mg ++ and the like.
  • Preferred compounds of formula I are those in which X is oxygen; further preferred are those in which R 1 is halogen, especially fluorine.
  • 6-Fluoro-8-acetamido-2,3-dihydrospiro[4H-1-benzopyran-4,5'-thiazolidine]-2',4'-dione and ( ⁇ )-methyl-6-fluoro-2,3-dihydro-2',4'-dioxospiro[4H-1-benzopyran-4,5'-thiazolidine]-8-carbamate are of particular interest.
  • the compounds of formula I and their salts can be obtained as racemates and in optically active form.
  • Optically active compounds of formula I can be obtained from the racemates in a known manner by racemate resolution, for example, by chromatography on an optically active carrier or by reaction with optically active bases, such as brucine, separation of the diastereomeric salts by fractional crystallization and conversion of the salt into the free acid, that is, the optically active compound of formula I. They can also be obtained by using an optically active compound of formula II as the starting material.
  • the optically active compound of formula II can be obtained, in turn, by racemate resolution.
  • the hydrolysis of the imino group in a compound of formula II can be carried out by treatment with strong acids for example, mineral acids, such as aqueous-alcoholic hydrochloric acid, preferably while heating up to the reflux temperature of the reaction mixture.
  • strong acids for example, mineral acids, such as aqueous-alcoholic hydrochloric acid
  • R 1 is halogen or hydrogen and R 2 is hydrogen
  • R 2 is hydrogen
  • This nitration can be carried out in a known manner for the nitration of aromatic compounds, for example, by treatment with a nitrating agent such as strong nitric acid at temperatures in the range of about -20° C. to about room temperature.
  • a compound of formula I wherein R 1 is halogen and R 2 is nitro can be reduced in a known manner for the reduction of aromatic nitro compounds.
  • Suitable reducing agents are, for example, hydrogen in the presence of catalysts, especially noble metal catalysts, such as, platinum oxide or palladium catalysts; or nascent hydrogen, for example iron/HCl, Raney-nickel; or ammonium sulfide in aqueous alcohol.
  • the amino group R 2 in a thus-obtained compound of formula I can be alkylated or acylated in a known manner by treatment with an alkylating agent or an acylating agent.
  • Suitable alkylating agents are alkyl halides, such as, methyl iodide or ethyl iodide in the presence of a base, such as, potassium carbonate or pyridine in an inert solvent, for example, ethanol.
  • acylating agents are reactive acid derivatives, such as, acid anhydrides, acid halides, activated esters, for example, nitrophenyl esters.
  • the replacement of the amino group by the cyano or hydroxy group can be carried out in a known manner by diazotization and reaction of the diazonium salt with copper (I) cyanide or, for the purpose of introducing the hydroxy group, with copper salts such as copper (II) nitrate by copper (I) catalysis.
  • the acyl groups --COOR 4 and --CONHR 4 can be introduced by reacting a compound of formula I in which R 2 is an amino or hydroxy group with an isocyanate of the formula R 4 NCO or a chloroformic acid ester of the formula R 4 OCOCl.
  • a compound (I) can be converted into the compound (2) by treatment with acrylonitrile in the presence of a base, such as, sodium methylate while heating to reflux temperature. Hydrolysis of the nitrile (2) by heating to reflux with strong aqueous hydrochloric acid yields the compound (3) from which (4) is obtained by treatment with hot polyphosphoric acid.
  • the synthesis of the thiazolidine group proceeds stepwise via a Peterson olefination with 2-lithio-2-trimethylsilyl-1,3dithiane to yield the compound (5).
  • the compounds of formula I and their salts are physiologically active, particularly, as aldose reductase inhibitors.
  • the compound of formula I in which R 1 is fluorine and R 2 is hydrogen was investigated for its activity on galactosaemic rats (30% galactose diet). More particularly, the dulcitol concentration in the eye lens was determined after 5 applications of 5 and of 20 mg/kg body weight per os over 2 days. Similarly, 20 mg/kg were administered intraperitoneally in an additional experiment. In all experiments, a significant decrease in the dulcitol concentration in the eye lens was established by comparison to untreated galactosaemic animals. The same compound was also administered to streptozotocin-treated, diabetic rats (3 times 20 mg/kg p.o., 4, 8 and 24 hours after streptozotocin administration). Three (3) hours after the administration of the last dosage, the sorbitol concentration was determined in the eye lens and in the sciatic nerve. In both organs a clear decrease in the sorbitol concentration was detected as compared to treated, diabetic animals.
  • the compounds of formula I and their physiologically compatible salts can be used as active substances in pharmaceutical preparations. More particularly, they can be used for the treatment of diabetes mellitus and for the prevention of complications, such as, cataract and neuropathies which appear due to such disease condition.
  • the compounds can be administered orally or parenterally in dosages of 0.1-5 mg/kg body weight giving due consideration to the mode of administration and the requirements of the patient.
  • the pharmaceutical preparations can be administered, for example, in the form of tablets, dragees, capsules, infusion solutions, eye drops or eye ointments, which besides the active substance can contain adjuvants and carrier materials which are conventional in such preparations.
  • the pharmaceutical preparations can be prepared using known galenical techniques.
  • the starting material was prepared as follows:
  • a tablet having the following composition can be prepared:
  • the ingredients are mixed and pressed into tablets which contain 20-200 mg of active substance.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
US06/619,655 1983-06-23 1984-06-11 Novel thiazolidine derivatives Expired - Fee Related US4587256A (en)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CH3432/83 1983-06-23
CH343283 1983-06-23
CH186084 1984-04-13
CH1860/84 1984-04-13

Publications (1)

Publication Number Publication Date
US4587256A true US4587256A (en) 1986-05-06

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US06/619,655 Expired - Fee Related US4587256A (en) 1983-06-23 1984-06-11 Novel thiazolidine derivatives

Country Status (11)

Country Link
US (1) US4587256A (fr)
EP (1) EP0129747A3 (fr)
AU (1) AU2947784A (fr)
DK (1) DK277484A (fr)
ES (4) ES8602820A1 (fr)
FI (1) FI842327A (fr)
HU (1) HUT34509A (fr)
IL (1) IL72139A0 (fr)
MC (1) MC1601A1 (fr)
NO (1) NO842515L (fr)
PT (1) PT78778B (fr)

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6812355B2 (en) 2002-10-22 2004-11-02 Sekhsaria Chemicals Limited Process for the manufacture of citalopram hydrobromide from 5-bromophthalide
US20050004077A1 (en) * 1999-12-22 2005-01-06 Tao Jiang Novel bisamidate phosphonate prodrugs
US20080070868A1 (en) * 2004-08-18 2008-03-20 Metabasis Therapeutics, Inc. Novel Thiazole Inhibitors of Fructose 1,6-bisphosphatase
US20090177267A1 (en) * 2007-11-15 2009-07-09 David Paul Biggs Medical devices and methods for local delivery of angiotensin II type 2 receptor antagonists
US7563774B2 (en) 2000-06-29 2009-07-21 Metabasis Therapeutics, Inc. Combination of FBPase inhibitors and antidiabetic agents useful for the treatment of diabetes
US20110082107A1 (en) * 2004-05-24 2011-04-07 Amgen Inc. Inhibitors of 11-beta-hydroxy steroid dehydrogenase type 1
US8686011B2 (en) 2004-05-24 2014-04-01 Amgen Inc. Inhibitors of 11-β-hydroxy steroid dehydrogenase type 1
CN115322208A (zh) * 2021-05-10 2022-11-11 中国药科大学 一类新型的2-氨基噻唑类衍生物及其制备方法和医药用途

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4537892A (en) * 1983-09-14 1985-08-27 Alcon Laboratories, Inc. Spiro-tricyclicaromatic succinimide derivatives as inhibitors of aldose reductase
JPH06772B2 (ja) * 1984-07-09 1994-01-05 鐘淵化学工業株式会社 ３―（４―フルオロフエノキシ）プロピオニトリルを用いる６―フルオロ―４―クロマノンの製造法
JPS61200991A (ja) * 1985-03-04 1986-09-05 Sanwa Kagaku Kenkyusho:Kk スピロ―３―ヘテロアゾリジン化合物、その製法及びそれを有効成分とする糖尿病合併症の予防及び治療剤
AU617541B2 (en) * 1988-10-20 1991-11-28 Wyeth Spiro-isoquinoline-pyrrolidine tetrones and analogs thereof useful as aldose reductase inhibitors
US6756360B1 (en) 1998-12-24 2004-06-29 Metabasis Therapeutics, Inc. Combination of FBPase inhibitors and insulin sensitizers for the treatment of diabetes

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4210756A (en) * 1976-10-18 1980-07-01 Pfizer Inc. Tetrahydroquinoline hydantoins for chronic diabetic complications
US4200642A (en) * 1978-08-21 1980-04-29 Pfizer Inc. Spiro-oxazolidindiones
US4226875A (en) * 1979-04-02 1980-10-07 Pfizer Inc. Novel spiro-oxazolidinediones
US4248882A (en) * 1980-02-12 1981-02-03 Pfizer Inc. Treating diabetes-associated complications with hydantoin amines

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Sohda et al., Chem. Pharm. Bull. 30 3601 (1983). *

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050004077A1 (en) * 1999-12-22 2005-01-06 Tao Jiang Novel bisamidate phosphonate prodrugs
US20090192121A1 (en) * 1999-12-22 2009-07-30 Tao Jiang Novel bisamidate phosphonate prodrugs
US7563774B2 (en) 2000-06-29 2009-07-21 Metabasis Therapeutics, Inc. Combination of FBPase inhibitors and antidiabetic agents useful for the treatment of diabetes
US20090197836A1 (en) * 2000-06-29 2009-08-06 Van Poelje Paul D Combination of FBPase Inhibitors and Antidiabetic Agents Useful for the Treatment of Diabetes
US6812355B2 (en) 2002-10-22 2004-11-02 Sekhsaria Chemicals Limited Process for the manufacture of citalopram hydrobromide from 5-bromophthalide
US20110082107A1 (en) * 2004-05-24 2011-04-07 Amgen Inc. Inhibitors of 11-beta-hydroxy steroid dehydrogenase type 1
US8686011B2 (en) 2004-05-24 2014-04-01 Amgen Inc. Inhibitors of 11-β-hydroxy steroid dehydrogenase type 1
US20080070868A1 (en) * 2004-08-18 2008-03-20 Metabasis Therapeutics, Inc. Novel Thiazole Inhibitors of Fructose 1,6-bisphosphatase
US20090177267A1 (en) * 2007-11-15 2009-07-09 David Paul Biggs Medical devices and methods for local delivery of angiotensin II type 2 receptor antagonists
US7828840B2 (en) 2007-11-15 2010-11-09 Med Institute, Inc. Medical devices and methods for local delivery of angiotensin II type 2 receptor antagonists
CN115322208A (zh) * 2021-05-10 2022-11-11 中国药科大学 一类新型的2-氨基噻唑类衍生物及其制备方法和医药用途
CN115322208B (zh) * 2021-05-10 2023-04-11 中国药科大学 2-氨基噻唑类衍生物及其制备方法和医药用途

Also Published As

Publication number Publication date
DK277484D0 (da) 1984-06-04
FI842327A (fi) 1984-12-24
IL72139A0 (en) 1984-10-31
FI842327A0 (fi) 1984-06-08
ES8602718A1 (es) 1985-12-01
ES533624A0 (es) 1985-12-16
DK277484A (da) 1984-12-24
ES541705A0 (es) 1985-12-01
NO842515L (no) 1984-12-27
ES541708A0 (es) 1985-12-01
ES541707A0 (es) 1985-12-01
AU2947784A (en) 1985-01-03
PT78778A (en) 1984-07-01
ES8602716A1 (es) 1985-12-01
EP0129747A3 (fr) 1985-09-25
ES8602719A1 (es) 1985-12-01
PT78778B (en) 1986-09-15
HUT34509A (en) 1985-03-28
ES8602820A1 (es) 1985-12-16
EP0129747A2 (fr) 1985-01-02
MC1601A1 (fr) 1985-05-09

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